Children's Hospital Capital Institute of Pediatrics, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Biochemistry and Immunology, Capital Institute of Pediatrics, Beijing, China; Graduate School of Peking Union Medical College, Beijing, China.
Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Mol Cell Endocrinol. 2024 Oct 1;592:112283. doi: 10.1016/j.mce.2024.112283. Epub 2024 May 28.
Adipose tissue macrophages (ATMs) are key players in the development of obesity and associated metabolic inflammation, which contributes to systemic metabolic dysfunction, and understanding the interaction between macrophages and adipocytes is crucial for developing novel macrophage-based strategies against obesity. Here, we found that Legumain (Lgmn), a well-known lysosomal cysteine protease, is expressed mainly in the ATMs of obese mice. To further define the potential role of Lgmn-expressing macrophages in the generation of an aberrant metabolic state, Lgmn; LysM mice, which do not express Lgmn in macrophages, were maintained on a high-fat diet (HFD), and metabolic parameters were assessed. Macrophage-specific Lgmn deficiency protects mice against HFD-induced obesity, diminishes the quantity of proinflammatory macrophages in obese adipose tissues, and alleviates hepatic steatosis and insulin resistance. By analysing the transcriptome and proteome of murine visceral white adipose tissue (vWAT) after HFD feeding, we determined that macrophage Lgmn deficiency causes changes in lipid metabolism and the inflammatory response. Furthermore, the reciprocity of macrophage-derived Lgmn with integrin α5β1 in adipocytes was tested via colocalization analyses. It is further demonstrated in macrophage and adipocyte coculture system that macrophage derived Lgmn bound to integrin α5β1 in adipocytes, therefore attenuating PKA activation, downregulating lipolysis-related proteins and eventually exacerbating obesity development. Overall, our study identified Lgmn as a previously unrecognized regulator involved in the interaction between ATMs and adipocytes contributing to diet-induced obesity and suggested that Lgmn is a potential target for treating metabolic disorders.
脂肪组织巨噬细胞（ATMs）是肥胖和相关代谢炎症发展的关键参与者，这导致了全身代谢功能障碍，了解巨噬细胞和脂肪细胞之间的相互作用对于开发针对肥胖的新型巨噬细胞策略至关重要。在这里，我们发现组织蛋白酶 L（Lgmn），一种众所周知的溶酶体半胱氨酸蛋白酶，主要在肥胖小鼠的 ATMs 中表达。为了进一步确定表达 Lgmn 的巨噬细胞在产生异常代谢状态中的潜在作用，我们在高脂肪饮食（HFD）下维持不表达巨噬细胞中 Lgmn 的 Lgmn; LysM 小鼠，并评估代谢参数。巨噬细胞特异性 Lgmn 缺乏可保护小鼠免受 HFD 诱导的肥胖，减少肥胖脂肪组织中促炎巨噬细胞的数量，并缓解肝脂肪变性和胰岛素抵抗。通过分析 HFD 喂养后小鼠内脏白色脂肪组织（vWAT）的转录组和蛋白质组，我们确定巨噬细胞 Lgmn 缺乏导致脂质代谢和炎症反应发生变化。此外，还通过共定位分析测试了巨噬细胞衍生的 Lgmn 与整合素α5β1 在脂肪细胞中的相互作用。在巨噬细胞和脂肪细胞共培养系统中进一步证明，巨噬细胞衍生的 Lgmn 与脂肪细胞中的整合素α5β1 结合，从而减弱 PKA 激活，下调脂肪分解相关蛋白，最终加剧肥胖的发展。总体而言，我们的研究确定 Lgmn 是一种以前未被识别的调节因子，参与了 ATMs 和脂肪细胞之间的相互作用，导致饮食诱导的肥胖，并表明 Lgmn 是治疗代谢紊乱的潜在靶点。
